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Sunday, January 26, 2014

After having
shown for some time now deep and long-lasting gene knockdown in lung endothelial
cells, Silence Therapeutics has finally published (Fehring et al. 2014) more
detailed chemical and pharmacokinetic information on the DACC formulation. This
formulation could be useful for indications such as cancer involving the lung
and acute lung injury.

Chemistry: cholesterol replaces helper phospholipid DPhyPE

Atuplex has long been the workhorse delivery technology of Silence Therapeutics. Atuplex has been
shown to target pretty much all vascular endothelial cells independent of tissue/organ
system and enables the company's lead candidate, Atu027 for the prevention of cancer metastasis currently in phase Ib/IIa in combination with gemcitabine in pancreatic cancer. Unlike the four-lipid
formulation pioneered by Tekmira, Atuplex consists of just three lipids:

To my
surprise, the DACC formulation contains the same cationic and pegylated lipids
as Atuplex. The main difference is in
replacing the helper phospholipid DPhyPE with another helper lipid, in this case
cholesterol. With this change (and some
adjustments in the lipid ratios), 40% of the DACC ends up in the lung with the
concomitant silencing of genes in resident endothelial cells.

Silence
Therapeutics’ strategy of utilizing a given cationic lipid in new lipid
combinations therefore stands in contrast to previous efforts by the likes of
Tekmira and Dicerna which have focused on the discovery of new
cationic lipids to increase potency and the therapeutic index.

Rationale of DACC over Atuplex for lung endothelial RNAi not fleshed
out

Although the
new research clearly shows that the lung is the most important physical sink for DACC, the
study did not investigate whether this translates into a tissue-specific
knockdown effect as well [correction 28Jan14: Figure 4 of the paper does show preferential knockdown in endothelial cells of the lung versus other tissues]. This would be an important additional safety-related rationale for using DACC over
Atuplex for lung endothelial gene knockdown, especially for target genes that might have critical functions in normal physiology as well.

Atuplex, in contrast, has previously been shown to mediate lung endothelial gene knockdown,
not just in mice (as DACC in this study), but also non-human primates. What is more, the previous Atuplex studies
showed comparable (~70-80%) knockdowns at ~10-fold reduced dosages (0.3mg/kg vs 2.8mg/kg). It will
therefore be important to test whether lower dosages are feasible for DACC
knockdown in non-human primates, potentially with the use of slow infusions
instead of bolus injections as was the preferred method in the present study. And as is my pet peeve when it comes to
Silence’s delivery technologies, why not attempt them with other, non-AtuRNAi trigger
technologies when a factor of 2 could make all the difference in whether you
have an acceptable therapeutic window or not.

It should be
noted, however, that unlike Atuplex, DACC appears to have a more reliable
dose-response and seems to be tolerated at up to 6mg/kg so I trust that Silence
has good reasons for choosing DACC for programs such as acute
lung injuries (ALI). Based on the data revealed by the company thus far, it
appears that the ALI candidate Atu111 is the prime candidate to be Silence's next clinical development candidate.

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